The present invention generally relates to systems and methods for sono-thrombolysis and more specifically relates to systems and methods for sono-thrombolysis employing ultrasound intensity and temperature monitoring techniques.
The use of ultrasound to accelerate thrombolysis has been proposed for many years. In experimental studies, ultrasound has been used, in conjunction with thrombolytic agents to disrupt peripheral arterial and venous thrombi in animal models and to open artheroscelerotic occlusions of peripheral arteries in some patients. In early research experiments, the ultrasound was typically delivered through catheters to prevent damage to normal tissues near the site of the occlusion.
Ultrasound application has been studied for its effect in fibrinolytic therapy with a thrombolytic agent, such as a tissue-type plasminogen activator (t-PA). Studies have suggested that transcutaneous ultrasound energy, delivered in a continuous mode at high frequencies, may enhance the thrombolytic effect of some medicinal agents by promoting agitation of the clot, thereby exposing additional fibrin in the clot for binding with the medicinal agent.
Lauer et al, in Circulation, 1992, investigated the effects of ultrasound on t-PA induced thrombolysis both in vitro and in rabbit jugular veins. More recently, Furtuhata in the proceedings of 1st International Symposium of Sonodynamic Therapy, 2000, investigated early recanalization of ischemic circulation by thrombolytic method combined with drug and ultrasound, including acceleration of thrombolysis by transcranial ultrasonic irradiation in rabbit femoral arteries and also in vitro.
The early investigators employed relatively high intensity of ultrasound at the site of exposure. Possibly, the early investigators believed that significant levels of ultrasound were needed to accomplish acceleration of lysis in both in vitro and in vivo experiments. Various methods have been used to generally assess the amount of ultrasound intensity being delivered to a site. Typically, the methods employed to assess the intensity of ultrasound used to produce results of an experiment involved sampling of intensities either before and/or after the experiment, rather than during the experiment.
Despite advances made in the field of sono-thrombolysis, there are significant problems that are not addressed by the prior art. For example, the potential for thermal injury is a significant concern that cannot be overlooked, particularly when sono-thrombolysis is employed on a human patient for treatment of an acute stroke in the brain. The present invention addresses these and other concerns and provides significant advantages over earlier sono-thrombolytic therapy methods.
Accordingly, a method for treating a patient experiencing an acute stroke, heart attack, peripheral arterial, deep vein, or other peripheral vascular occlusion using sono-thrombolysis is provided.
The present invention generally comprises establishing an ultrasound delivery column to the subject or patient, and providing real-time monitoring of both intensity and temperature in order to limit energy exposure, avoid cavitation and control heating to prevent thermal injury to the patient. Preferably, the monitoring of the ultrasound intensity and the temperature is performed continuously during application of the ultrasound. By employing careful, real-time monitoring of characteristics of the ultrasound being delivered, effective thrombolysis of the occlusion can be accomplished using low intensity ultrasound preferably in conjunction with low concentrations of thrombolytic agents.
More specifically, a method of using ultrasound to treat a patient experiencing a thrombotic or embolic occlusion, in accordance with the invention, generally comprises the steps of establishing an ultrasound delivery column to the patient, wherein the column comprises an ultrasound transducer, a coupling medium and a hydrophone, operating the transducer to deliver ultrasound to the thrombotic occlusion and monitoring ultrasound intensity on a real-time basis with the hydrophone. In response to the monitored characteristics of the ultrasound, intensity of the delivered ultrasound is controlled within a desired intensity range, using conventional electronics equipment and techniques.
The ultrasound energy is preferably provided by a ultrasound transducer assembly, utilizing, for example, a 27 kHz transducer. Preferably, pulse mode ultrasound, rather than continuous mode ultrasound, is employed for sono-thrombolysis therapy in accordance with the present invention. Preferably, the pulse mode is set at a 10% duty cycle. By using pulse mode ultrasound, average intensity delivered is reduced in comparison to levels that would be delivered using continuous mode ultrasound. The efficacy of pulse mode versus continuous mode is higher per unit of intensity delivered. Therefore, pulse mode is more desirable in terms of efficiency. Pulse average intensity is the time averaged intensity, in watts per square centimeters, during the ultrasound pulse. Temporal average intensity is the pulse average intensity multiplied by the pulse length, and divided by the time between pulses.
The desired intensity of the ultrasound preferably has a pulse average intensity of up to about 1 watt/cm. More preferably, the ultrasound has a temporal average intensity of about 0.25 w/cm2 and the ultrasound intensity range may be a range of between about 0.06 w/cm2 and about 0.25 w/cm2 temporal average intensity. At these relatively low levels of ultrasound energy, infarction volumes of patients who are experiencing an acute stroke can be significantly reduced as will be described hereinafter.
It is noted that the actual intensity of ultrasound being delivered to the patient is influenced by many factors. For example, small variations in the contact surface (i.e. contours or shape of the body surface of the patient on which the transducer is positioned), the viscosity and entrapped air of the coupling medium, the force being applied to the transducer to ensure good contact between the transducer and the patient, all can cause significant variations in the intensity of ultrasound being delivered.
Ideally, in accordance with the invention, the hydrophone is positioned between the transducer and the subject in order to provide accurate measurement of ultrasound intensity as the energy enters the subject. Characteristics of the ultrasound can be viewed by means of a conventional oscilloscope assembly connected to the hydrophone. Intensity of the ultrasound can be adjusted by the operating technician to ensure the intensity remains within the desired range (e.g. between about 0.06 w/cm2 and about 0.25 w/cm2). Actual oscillographic plots of intensity may show a waveform with occasional spikes that are attributable to the presence of cavitation occurring at the site of exposure. High levels of cavitation at the site of exposure may cause excessive heating of the patient and therefor should be minimized.
Preferably, therefore, the coupling medium used should be selected to reduce or minimize the occurrence of cavitation. Specifically, in accordance with the present invention, the coupling medium may comprise a silicone material, and a thin layer of glycerine on either side thereof. Even more specifically, the hydrophone is preferably encased within a silicone material, for example a pellet of silicone material. To provide sufficient coupling, a thin layer of glycerin is placed on either side of the silicone pellet having the hydrophone encased therein. The silicone pellet and thin layer of glycerin is positioned between the transducer and the body surface of the patient. It has been found that when silicone and glycerin are used in this manner as the coupling medium, cavitation is reduced, in comparison to other more conventional coupling media such as the medium known as xe2x80x9cSonigelxe2x80x9d.
Temperature rise is a significant concern, especially for patients exposed to ultrasound who are experiencing an acute stroke. Hypothermia has been proposed as a method to reduce damage caused by an acute stroke. Ideally, in accordance with the present invention, the application of the ultrasound would have no effect on temperature rise of the exposed patient. Practically, a temperature rise of about 1 deg C. to about 2 deg C. may be tolerated, but no greater. In a highly advantageous embodiment of the invention, the method further comprising the step of monitoring temperature of the patient on a real-time basis, wherein the temperature is monitored proximate the site of the occlusion. This embodiment of the present invention therefor includes the step of monitoring temperature on a real time basis.
This feature of the present invention is particularly important when the method is employed for treatment of a patient experiencing an acute stroke. The step of monitoring temperature may include placing a temperature probe external to the skull of the patient, with the hydrophone in the silicone material. Temperature can be monitored on a real time, continuous basis for the purpose of limiting temperature rise and avoiding damage to the brain of a patient undergoing an acute stroke.